PROJECT SUMMARY/ABSTRACT The recent groundbreaking experiment using a single neutralizing monoclonal antibody (nmAb) to reduce the death rate in Ebola virus (EBOV)-infected individuals highlights the importance of this class of drug in the treatment of infectious disease. In August 2019, Dr. Anthony Fauci announced that administration of mAb114 had reduced the death rate from 70% to approximately 35% in EBOV-infected patients. EBOV infection is no longer considered a uniformly fatal disease. Similar to EBOV infection, wild-type yellow fever virus (wtYFV) infection results in high viral loads and a death rate of up to 50% in hospitalized patients. Once infected, there is no current treatment available. While the YFV17D vaccine is generally efficacious, it has some potentially severe side effects which diminish its coverage. Unfortunately, the World Health Organization (WHO) reported approximately 100 cases of severe adverse effects due to mass vaccination campaigns in Brazil, dissuading many people from receiving the vaccine. Even though vaccination campaigns were launched, immunization coverage remains low, leaving a significant number of people at risk. Most of the world, including the U.S., is vulnerable to mosquito-transmitted diseases, as shown by the emergence of two related flaviviruses dengue (DENV) and Zika (ZIKV). At Mabloc LLC, through our collaborations with the Watkins, Kallas and Burton laboratories, and Adimab LLC, we have assembled a large collection of flavivirus-specific neutralizing monoclonal antibodies (nmAbs). Indeed, the Watkins laboratory has already shown that these mAbs can be used for the prevention and treatment of flavivirus infections. The Watkins and Burton laboratories, and more recently others, have demonstrated that ZIKV infection can be prevented in Indian rhesus macaques by using either a nmAb cocktail or a single nmAb. Additionally, the Watkins and Burton laboratories have also shown that this cocktail can reduce viral load to undetectable levels in ZIKV-infected pregnant macaques. These data demonstrated, for the first time, that post-exposure treatment with nmAbs can reduce flavivirus replication in a relevant non- human primate (NHP) model. In Phase I of this application, we plan to identify at least five nmAbs from our existing pool of mAbs for wtYFV treatment using in vitro assays and in vivo screening in Syrian golden hamsters. In Phase II, we will perform tissue cross reactivity studies using our best YFV-specific nmAbs. We will then test the efficacy of the best three nmAbs in treating wtYFV-infected monkeys. After the completion of this Fast-Track Phase I/II application, we plan to have at least a commercially viable cocktail or a single nmAb that can efficaciously suppress viral replication in wtYFV-challenged NHPs, and thereby save them from the sequelae of wtYFV infection, namely death.